Acetylation of thiophene compounds



United 4 States.

2,711,414 ACETYLATIQN or Ted R. Norton, Concord, Califl,

Chemical Company, Midlanmlflicha a corporation of V 4 Delaware N w n A p cation. Sinteiuhe 12 r S l.NQ-,2 8

8 Claims. (cl. 260993323) 3 e r H Thisinvention concerns an improued method and cer tain catalysts for reactingacetic anhydride withthiophene; and with alkylated thiophene's which are unsubstituted acetylated derivatives thereof. 1

in the 2-position of' the thiophene"nucleus,- td form It is known that thiophene may he. aeylated by reaction with organic carboxylic acid anhydridesoncpnrespond ing' acyl halides in the presence of catalysts," andthatfthe results obtained vary widely depending uponzthe- 'reaction conditions, particularly.- the kind and proportionof catalyst, employed A variety of*eatalysts,-e. ?g. ialumi:-

num chloride, stannic chloride, pentoxide, iodine, zinc chloride; sulphuric acid; phosphoricacid," acid-activated bleaching earth, glaucinitegand dihydroxyfluoboric acid, 'etc.,"haveheen disclqsndas enecavean such reactions. In most, iii not all, instancesthe known 30 methods for the aeylation, of'thioph'ene involve'one bi T I an more disadvantages, suehwas: formationfof zthe-idesired product inlow yield: ainclf-often accompaniedi bywlarfge amounts of tarry bYrPl'OdLlCtS, a-requirementthat catalyst be used in largeproportion relativettiz'the amountsof materials to be, IGQCIQ r. occurrence 1 of rapid- \deactivaetion or poisoningof the catalysts rendering it unsuitable" cy a io ea n atalowirate; etc- I has no been. found tha e insoluble, uclea sulph nated owlymer1 for further use inthe process, and occurrence meme idedp-water-a and polyvinyl-aromatic hydrocarbons, such as are disclosed as cation exchange materials in U. S. Patent No. 2,366,007, are exceptionally effective'as catalysts for the reaction/of, acetic anhydride withthiophene, and with a y ated thienhenes. which. vthe; un uhstitutedin the, 21

position of the thiophe'ne nucleus, to form correspond; ing acetylated thiopheneiiconipoiindsf:Such.catalyst are effective, even when employed in small proportionyin" causing the acetylation to occur r apidly'at"moderately elevated temperatures to form theacetylated thiophene e a e n h e d nd. m rcadil pn itie zle onn- A t r o p ti g he rca iq t the satsl st n 1? ve by filtering qr dec nt g; mummies, no pur y dis l at on Th te vw ca l st a u l ye p oy drqne ma imesrh fats' becoming deactivatedftota point where suitable for use; in the eactiQn f-By w n emp y n 4911 ca alyst ,l

u y h bq eem gnsd. sulu wimp :11 mar of o ny a ;n 1y ;in l:aramanq=lasl n ar i is o lenses; t

bans, l o ptiqna l e w iv as alyst the reaction o ce i ai h dti erwi i thioeh eand s mple tiont h a e been found be' na t e,

r es he p r ab v peq fic su h a 3852- activity, when tested as catalysts for other a re; actions n o v n QPh For nsta 1 ul phona ed c po ym r ai ed; cause. a tea t r of pr s nic;

anhydride. h h onhe evunslsr cons! IQHS: milar: 1 hos a hich hc-sa nca alyst a 8 p v n :nearlu comnleteraas onofiaedia a hvdr. It caused formation'of -2-acetylthiophene in ;low yield,

are no V w 'ghl 70 v Patented June 21, 1955 i. e; a lessthan 15 percent yield, when tested under other} i wi'sei-similaf conditions asia catalyst for thereaction ofactylachlqrideflwitgh fthiophene. The reason why the aboveimentiqned,siilphonatedcopolymersare speci-ficas V catalysts'ifor thelivre action of z acetic anhydride-with'thiophene and. simple'derivatives thereof is not known, but itis probable 'thatthe' sulphonated,=copolymer catalysts isonqd; i-IiQ. deactivated, :to a greatjlextent' dur-i ins eimsuchfi ac ns, ut are-r pidlyfpoisoned when me. for

mama andvpolyv ylea omatici hydrocar ons have;

been; foun o e far more. ffective than o her. 5' catio 7 exchang ma erial s ata y for theiracti n-oface ic ri ewith hbphene; For n an e:asulp w 1 io m s shydere aus d form ion of 2.acetylv fiioghene in alessthanj per centyield; and a car boxylav ed; phenolfiq rnalglehyde,v resin failed tof cause, any reac-z,

tie ,when; tested asicatalysfts" for the reaction of, acetic anhyglriglev with thiophene; under conditions similar to, those at which the sulphonated cop ar hish r eiieetive inrpr oti si c c mathsenucl ar su phonat 'coPmymfl pf '7 and polyvinylgarqmatie compounds. whicharefadapn e a d n aqueous solutionsof;acidsEor"alk lies; catalysts; in the-process ofithe invention;

ato em d lcs sa numberof uch su phonatedopo m de sribee lten pa tion o t hei j me- Cop 'ymi rs oi styrene with from 1 to 20 percent.byivveight ofidivinyl-i p and .cenc y ers of tyrene, ar-e hy 'i' y c c V, b t V nd i o 1-; 9

uming, si pliu a e. well s ite sulphonic acid'radical per aromaticnucle'us', but the-"p d? uctamay be of lowereri somewhat higher sulphonic acid radical, contentfie; or more sul'pho a cid' radical er aromaticnucleus;

The. catalytj ca se i the a sty i l refbr t s rta a ago fhe s r t A c d ngl :al hp te c pol m r granu e may b of any a greate nfiaqsr ca, than. ma er h m esh 1 $1 hiQll li d. q p lymer g'ram na 7, n

er than throughout the granules,

s n t; ne sl the, reactiong'of thiopjhene with. Other acylatmg above-mentioned; mu na edi" p y n sio 3% asfjon; exchangejagentsi. e'.,which;are-insolu-;

:reactibn with concentrated 1 1 Q9. ta diprchlorosulphonic; 1 lphonated' copolymer 7 products "which" .18;: in the processn; In most instances; the sulphonation is, carried to1a point; at whicli the sul -g' alienated: QPDlymerpcontainsLanfaverage of about; one 3 may 3 contain an average of 0.5;

t Y? P wi h. s angain the, i I,

uAp parentlyg Pal y at. t e E'Q i e rface therleofi T i thec d. Qrm h= ul'p onat i c p xme l ca e-as.ea elvstinft ep oc ss? It' 'h c hat'thesulphonated' copIoly-Q pine its." acid, 'fprr-n'fwhenemployed asa 7 catalyst, i. e. a sulphonated copolymer which ha s been I shape of the catalyst particles.

only partially converted to its acid form from a salt form of the same may be used as the catalyst.

The minimum proportion of the catalyst required t cause a rapid reaction of acetic anhydride with thiophene varies with changes in the sulphonic acid radical content of the catalyst, the particlue size of the catalyst and the When using the crushed or ground sulphonated copolymer in a finely divided form capable of passing through a 200 mesh Tyler screen, as little as 0.4 gram of catalyst per gram mole of the acetic anhydride reactant has been found sulficient to permit a fairly rapid reaction of the acetic anhydride with thiophene to form Z-acetylthiophenonein appreciable yield, and as little as 0.1 gram of the catalyst per gram mole of the acetic anhydride caused the reaction to occur slowly, but at an appreciable rate. However, it has been observed that the yields of Z-acetylthiophene are somewhat higher when the reaction is carried out rapidly than when carried out slowly but over a longer period of time. For this reason, it is preferable that the catalyst be used in amount sufficient to cause a rapid reaction. In practice, 1 gram or more, e. g. from 1 to 5 grams, of the finely divided catalyst is usually employed per gram mole of the acetic anhydride. The catalyst may, of course, be used in much larger proportions, e. g. as large as desired.

The catalytic acetylation of thiophene and simple derivatives thereof is carried out, preferably under reflux, at reaction temperatures of 75 C. or above, usually at temperatures of between 80 and 125 C., but it may be carried out under pressure, i. e. in a closed vessel, at higher temperatures. Also, the reaction is usually carried out in the absence of liquid solvents or diluents other than the reactants themselves, but an inert liquid diluent, e. g. acetice acid, may be used as a reaction medium if desired.

The reactants may be used in any desired proportions, but, under otherwise similar conditions, the reaction occurs more rapidly and favorably when either of the reactants, particularly the thiophene, is used in a molecular excess over the other than when the reactants are used in equimolecular proportions. Usually, from 1.2 to 3 gram molecular equivalents or more of thiophene is employed as a starting material per mole of the acetic anhydride.

The reactants and catalyst may-be admixed with one another in any desired order. For instance, they may be mixed at room temperature and the entire mixture be heated to the reaction temperature, or a mixture of the thiophene and catalyst may be added with stirring to the heated acetic anhydride, etc.

When operating under the preferred conditions set forth above, the reaction may be carried nearly to completion in less than two minutes, but in practice the mixture is usually stirred and heated for a longer time, c. g. from to 30 minutes or more,'so as to assure substan-' tially complete reaction. The catalyst is then removed, e. g. by filtration, and the reaction liquor is distilled to separate the acetylated product and to recover any unreacted thiophene or acetic anhydride. The recovered thiophene or acetic anhydride may be returned to the reaction.

The process may be carried out batchwise, as just described, or in a continuous manner. The process may be carried out continuously by passing a suspension of the catalyst in the reactants through a reaction zone where it is heated at the reaction temperature, e. g. for from 2 to 10 minutes. The mixture flowing from the zone is filtered to remove the catalyst and fractionally distilled to separate the product and recover unreacted starting materials.

The process may be applied in reacting acetic anhydride with thiophene, or with any nuclear alkylated thiophene which is unsubstituted in the 2-position of the nucleus, e. g. with a S-alkylthiophene, to form a correthe invention has been practiced, but are not to be construed as'limiting its scope.

- EXAMPLE 1 In each of three experiments a mixture of 51 grams (0.5 mole) of acetic anhydride, 126 grams (1.5 moles) of thiophene and a minor amount ofa finely ground,

sulphonated copolymer of styrene, ar-ethylvinylbenzene and divinylbenzene was stirred and heated at 96 C. under reflux for 15 minutes. was one prepared by sulphonation of a copolymer of about 84 per cent by weight styrene, about 8 per cent ar-ethylvinylbenzene and about 8 per cent divinylbenzene. It contained an average of approximately one sulphonic acid radical per aromatic nucleus. The sulphonated copolymer was employed in its acid form. The amounts of the sulphonated copolymer used in the three experiments were 0.05 gram, 0.2 gram and 0.5 gram, respectively. After each mixture had been heated at 96 C. for 15 minutes, it was cooled, filtered to remove the catalyst, and the filtrate was fractionally distilled to recover unreacted thiophene and to separate the Z-acetylthiophene product. The amount of thiophene not recovered as such was assumed to have been consumed. The conversion of starting materials in each experiment is calculated by dividing the gram molecular equivalents of thiophene consumed in the reaction by the gram molecular equivalents of acetic anhydride employed as a start-' ing material. The per cent yield on consumed material is obtained by dividing the gram molecular equivalents of Z-acetylthiophene by the gram molecular equivalents of thiophene consumed in the reaction and multiplying by 100. The per cent etficiency obtained in each experiment is the arithmetical product of the conversion and the per cent yield. The following table gives the grams of catalyst employed in each experiment and the per cent efficiency of the reaction in said experiment.

Table I Grus. of Percent; Run No Catalyst Etficiency EXAMPLE 2 mixture was cooled and filtered. The filtrate was fractionally distilled to recover unreacted starting materials and acetic acid formed in the reaction and to separate the Z-acetylthiophene product. The amount of higher boiling by-products was determined by weighing the residue which remained after the Z-acetylthiophene had been distilled. The conversion, per cent yield and per cent efliciency values for each experiment were calculated as in Example 1, except that the conversion was obtained by dividing the gram moles of consumed thiophene by the gram molecular equivalents of the reactant (i. e.

thiophene or acetic anhydride) which was used in lesseramount in the starting mixture. Table IIgives the gram molecular equivalents of acetic anhydride and thiophene The sulphonated copolymer employed as starting materials,

lsent via" efliciency for each expo is ba 'f a 9 a ezperiuspt- Gm. Moles of- Run r Con- Percent 'Glns.ot gg e Thto-- as en X1 1 Residue fi s; phene 1': will Bhkitd 1L5? a; yam "2-.a1.i.a e.;; is, .i higher and the efiiciency of the process greater when.

either of the reactants is used inmolecularexcessover q, a Y aim-an the other, and that these improvements are greatestwhen f it is the thiophene which is used in excess. It will also be noted that by-products are formed in only small amount in practice of the invention and'that the amount of high boiling by-products, i. e. tarry still residue, is. particularly small. t

EXAMPLE 3 K In each of two experiments, a mixture of 0.5 gram molecular equivalent of acetic anhydride, 1.5 gram moles of thiophene, and 4 grams of a finely dividedsulphonated copolymer having approximately the compositionot that described in Example 1 was boiled under reflux for 4.5

hours. The mixture was then cooled, filtered and the filtrate was distilled to recover unreacted materials and separate the Z-acetylthiophene product. The experim'ents difiered from one another in that the .sulphonated'copolymer employed as a catalyst in one experimentwas material which had been prepared directly as rounded particles of from 250 to.500 mesh size whereas the sul phonated copolymer used'in the other experiment con- 7 sisted of irregular shaped particles capable of passing a.

.for'the 'reaction a g 2. In a method" wherein Za' thiophene;cornpound,- of

Fem

out

vinyland pollyvinyl-aromatic hydrocarbons f as a catalyst the groupconsisting of thiophene and lower alkyl thiof phenes containing the alkyl radical as 'a substituent in the 5-position of the thiophene nucleus, is acetyl'ated by j reacting the" same with facetic anhy'drideatg a- -reaction 7 temperature between175 and 125? pgjtheirnprovementi of carrying out the reaction-in contact. with finelydi- V vided, nuclear sulfonated copolymer of monovinyl aand mesh screen, which particles had been'formed, by

grinding coarsermaterial. Table III identifies eachex form of rounded particles or irregular shaped particles periment by indicating whether the catalyst was in the}? and gives the per cent eificiencyobtained in each experiment. 7

' 'T able III Formtot Catalyst 9 Percent Run No Particles Eflieieney 1 Rounded-. 45.6 2 r; h'regular shaped 76.4

It will be evident from the table that in order to'obtain a given rate of reaction, a catalyst in the form ofrounded particles must be used inlarger proportionfthan is required when the catalyst is in the form of irregular'shaped particles of the same particles size. f

EXAMPLE4 A mixture of 28 grams (0.2. mole) of fi-(tertiarybutyl) thiophene, 21 grams (0.2 mole) ofacetic anhy dride and 0.5 gram of the finely ground .sulphonated.

copolymer described in 'Example 1, was stirred andheated under reflux at temperatures of from to b The;

l polyvinyl-aromatic. .hydrocarbons as .a catalyst while? agitating. .the' mixture I to cause dispersion of the catalyst in the mixture.

"f3." In a method I wherein. a lower alkylthiophene;

having the 'allcyl radicalas a substituent in the 5-posi-= tion'fof the thiophene nucleusjjs ac'etylated,-by reacting "the'same with acetic anhydride at 'axtemperature bei tween 75 and C., the improvement oi. carrying 0ut;the,;reaction in contact with a finely divided, nuclear sulphonated copolymer iof monovinyl-'-' andi'polyvinylaromatic hydrocarbons as: a catalyst, for the reaction. I j

4. In a method wherein 5-(tertiary-butyl') thiophene is acetylated by reacting the same with acetic anhydride at temperatures between 75 andlZS? CL, theirnpfovement of carrying out the reaction-in contactfwith a I finely divided nuclear sulfonated copolymer bfifmonoj- 'a- .vinyland polyvinyl-aromatic.hydrocarbons -,as{a'catalyst* for the reaction, said 'catalys't ,being present finflthe re-J action mixture and the latter'ffbeing stirred 'duringflthe f reaction.

' 45. In a method of'making .2 -acetylthiophenefwherein thiophene is 'acetylated by reacting'thesaniwithacetic; .anhydride, the improvements of carrying outfithe reaction by heating a mixture ofjthiophene, acetic'janhydride" and a minor amount of affinely dividedmuclear sul phonated copolymer of a' major amounttofq at least one monovinylgaromatic hydrocarbon and'a minor amount of divinylbenzene.atreaction temperatures between 75" andfi125f CL, thereafter removing the sulphonated copolymerwfrom the mixture.and fractionally distilling-the remaining mixture to. separate the 2-acetylthiophene V product.

6. In a method of making 2-acetylthiophenewherein thiophene is acetylatedbyreacting thelsame withsa'cetic. I

anhydride, the; improvements of carrying' outthe re-* action by agitating and heating a mixture of thiophene, "acetic anhydride and aminor amount of afinely-divided nuclearlsulphonatedfcopolymer of; a major amount of 'styrenefand minor amounts .of'ar-ethylvinylbenzene and" 'divinylbenzene, which copolymer is in thefor'm if irregu-f lar' shaped particles, at reaction temperatures between 70. move the sulphonated copolymer, and-fractionally dis- 1 tilling the filtrate} to separate the 2-acetylthiophene. 7

75 and 125 CI, the're'afte r filteringfthe mixture to reproductl V '7; In a methodof making Z-acetyl-S-(.tertiary-butyl) thiophene wherein} '5-(tertiary-butyl) thiophene isiacety V I lated by reacting the same with acetic anhydride, the

improvements of carrying out the reaction by heating a mixture of S-(tertiary-butyl) thiophene, acetic anhydride, and a minor amount of a finely divided nuclear sul phonated copolymer of a major amount of at least one monovinyl aromatic hydrocarbon and a minor amount of divinylbenzene at reaction temperatures between 75 and 125 C., thereafter removing the sulphonated copolymer from the mixture, and fractionally distilling the remaining mixture to separate the Z-acetyl-S-(tertiary-butyl) thiophene product.

8. In a method of making- 2-acetyi-S-(tertiary-butyl) thiophene wherein S-(tertiary-butyl) thiophene is acetylated by reacting the same with acetic anhydride, the improvements of carrying out the reaction by heating a mixture of S-(tertiary-butyl) thiophene, acetic anhydride and a minor amount of a finely divided nuclear sulphonated copolymer of a major amount of styrene and minor amounts of ar-ethylvinylbenzene and divinylbenzene, which copolymer is in the form of irregular References Cited in'the file of this patent UNITED STATES PATENTS Hartough et al. Dec. 23, 1947v OTHER REFERENCES Thomas et ai.: Nature, 159:372 (1947). V

Nachod: Ion Exchange, pp. 261-273, Academic Press 1110., N. Y., 1949. V

Emerson et al.: J. Org. Chem. 13, pp. 722-28 (1948); 

1. IN A METHOD WHERIN A THIOPHENE COMPOUND, OF THE GROUP CONSISTING OF THIOPHENE AND LOWER ALKYL THIOPHENES CONTAINING THE ALKYL RADICAL AS A SUBSTITUENT IN THE 5-POSITION OF THE THIPOHENE NUCLEUS, IS ACETYLATED BY REACTING THE SAME WITH ACETIC ANHYDRIDE, THE IMPROVEMENT OF CARRYING OUT THE REACTION IN CONTACT WITH A FINELY DIVIDED, NUCLCAR SULFONATED COPOLYMER OF MONOVINYL- AND POLYVINYL-AROMATIC HYDROCARBONS AS A CATALYST FOR THE REACTION. 